Methods Of Treating Overweight And Obesity

ABSTRACT

The present disclosure relates to compositions, kits, uses, systems and methods for treating overweight and obesity using naltrexone plus bupropion, preferably in combination with a comprehensive web-based and/or telephone-based weight management program, and preferably in subjects at increased risk of adverse cardiovascular outcomes.

RELATED APPLICATIONS

The present application is a continuation of U.S. application Ser. No.16/558,211, filed Sep. 2, 2019, which is a continuation of U.S.application Ser. No. 15/491,870, filed Apr. 19, 2017, now U.S. Pat. No.10,403,170, which is a continuation of U.S. application Ser. No.14/405,775, now U.S. Pat. No. 9,633,575, which is the U.S. NationalPhase under 35 U.S.C. § 371 of International Application No.PCT/US2013/044368, entitled “METHODS OF TREATING OVERWEIGHT ANDOBESITY,” filed Jun. 5, 2013, and published in English on Dec. 12, 2013as WO 2013/184837, which is a non-provisional of and claims priority toU.S. Provisional Application No. 61/656,451 filed on Jun. 6, 2012,which, where permitted, is herein incorporated by reference in itsentirety.

BACKGROUND Field of the Invention

The present disclosure relates to compositions, kits, uses, systems andmethods for treating overweight and obesity using naltrexone plusbupropion, preferably in combination with a comprehensive web-basedand/or telephone-based weight management program, and optionally insubjects at increased risk of adverse cardiovascular outcomes.

Description of the Related Art

Obesity has been defined in terms of body mass index (BMI). BMI iscalculated as weight (kg)/[height (m)]². According to the guidelines ofthe U.S. Centers for Disease Control and Prevention (CDC) and the WorldHealth Organization (WHO), for adults over 20 years old, BMI iscategorized as follows: below 18.5 is considered underweight, 18.5-24.9is considered normal, 25.0-29.9 is considered overweight, and 30.0 andabove is considered obese (World Health Organization. Physical status:The use and interpretation of anthropometry. Geneva, Switzerland: WorldHealth Organization 1995. WHO Technical Report Series).

The prevalence of obesity has markedly increased over the past threedecades, with 32% of men and 36% of women considered obese. Theseindividuals are at increased risk for a variety of chronic conditionsassociated with obesity, including type 2 diabetes, coronary heartdisease, hypertension, stroke, dyslipidemia, gallbladder disease, sleepapnea, certain types of cancer, and osteoarthritis, as well as increasedmortality risk from all causes (NHLBI Clinical Guidelines, 1998).Overweight and obesity are also associated with increased all-causemortality.

Diet and exercise-based behavioral modification is the mainstay ofweight management therapy. However, such intervention is often oflimited effectiveness and difficult for individuals to adhere to.Therefore, pharmacotherapy has been employed as an adjunct to diet andexercise. Orlistat, lorcaserin, and phentermine/topiramate are currentlythe only three drugs approved in the United States for the long-termtreatment of obesity. A 5-10% weight loss has been determined to lead tosignificant medical benefits. While orlistat has a favorable safetyprofile, it can cause loose stools and fecal incontinence, makingacceptance by patients difficult. Bariatric surgery (specificallygastric banding) is now indicated for subjects with BMI ≥30 kg/m² whohave at least one obesity-related comorbidity. While effective in mostcases, it is invasive with possible complications including infection,death, hypoglycemia, failure to lose weight, gastrointestinal symptoms,nutritional deficiencies, depression, sexual and relationship problems,and noncompliance with behavioral recommendations.

U.S. Pat. Nos. 7,375,111 and 7,462,626 disclose the combination ofnaltrexone and bupropion (NB) for weight loss therapy. Wadden et al.disclose the combination of naltrexone and bupropion as an adjunct to anintensive behavioral modification (BMOD) program for weight loss.Obesity (2011) 19:110-120. The BMOD program described by Wadden et al.was delivered in person to groups of 10-20 persons. Group meetingslasted 90 min and were held weekly for the first 16 weeks, every otherweek for the next 12 weeks, and monthly thereafter (yielding a total of28 sessions). Group sessions typically began with a review ofparticipants' eating and activity records and other homeworkassignments. Group leaders then introduced a new topic in weight controlwhich, during the first 16 weeks, included meal planning, stimuluscontrol, slowing eating, problem solving, social support, and copingwith high risk situations. Subsequent sessions covered skills requiredfor maintaining lost weight.

While the combination of naltrexone and bupropion is known to beefficacious for weight management for some patient populations, alone orin combination with an intensive BMOD program, a need exists for aneffective treatment of overweight or obesity in subjects at increasedrisk of adverse cardiovascular outcomes. In addition, there exists aneed for a weight management program for use in combination withnaltrexone and bupropion that is easier for patients to comply with thanexisting BMOD programs, but which is still efficacious, particularly insubjects at increased risk of adverse cardiovascular outcomes.

SUMMARY

An embodiment of the invention includes a method of treating a subjectat increased risk of an adverse cardiovascular outcome comprising foroverweight or obesity: identifying an overweight or obese subject atincreased risk of an adverse cardiovascular outcome; and administeringto the subject a therapeutically effective amount of sustained releasenaltrexone, or a pharmaceutically acceptable salt thereof, and sustainedrelease bupropion, or a pharmaceutically acceptable salt thereof. Insome embodiments, aid overweight or obese subject is identified as beingat increased risk of an adverse cardiovascular outcome if the subject:a.) is diagnosed as having cardiovascular disease with at least one riskfactor selected from the group consisting of: a history of documentedmyocardial infarction >3 months prior to the identification; a historyof coronary revascularization including coronary artery bypass graftsurgery, stent placement, percutaneous transluminal coronaryangioplasty, or laser atherectomy; a history of carotid or peripheralrevascularization, including carotid endarterectomy, lower extremityatherosclerotic disease atherectomy, repair of abdominal aorta aneurysm,femoral or popliteal bypass; angina with ischemic changes, ECG changeson a graded exercise test, or positive cardiac imaging study; anklebrachial index <0.9 assessed by simple palpation within prior 2 years ofthe identification; and ≥50% stenosis of a coronary, carotid, or lowerextremity artery within prior 2 years of the identification; and/or b.)is diagnosed as having Type 2 diabetes mellitus with at least 2 riskfactors selected from the group consisting of: hypertension controlledwith or without pharmacotherapy at <145/95 mm Hg; dyslipidemia requiringpharmacotherapy; documented low HDL cholesterol, <50 mg/dL in women or<40 mg/dL in men, within prior 12 months of the identification; andcurrent tobacco smoker.

In some embodiments, the method further comprises a lead-in 2-weekperiod during which the subject receive treatment according to one oftwo sequences: 1 week of active study medication comprising sustainedrelease naltrexone, or a pharmaceutically acceptable salt thereof, andsustained release bupropion, or a pharmaceutically acceptable saltthereof, once a day followed by 1 week of placebo once a day; or 1 weekof placebo followed by 1 week of active study medication comprisingsustained release naltrexone, or a pharmaceutically acceptable saltthereof, and sustained release bupropion, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the subject does not have one or morecharacteristics selected from the group consisting of: myocardialinfarction within 3 months prior to the identification; angina pectorisGrade III or IV as per the Canadian Cardiovascular Society gradingscheme; a clinical history of cerebrovascular disease including stroke;a history of tachyarrhythmia other than sinus tachycardia; bloodpressure ≥145/95 mm Hg, irrespective of treatment with antihypertensiveagents; unstable weight within 3 months prior to the identification;planned bariatric surgery, cardiac surgery, or coronary angioplasty;severe renal impairment defined by an estimated GFR <30 mL/min; clinicalhistory of liver failure or documented ALT or AST greater than 3 timesthe upper limit of normal; known infection with HIV or hepatitis;chronic use or positive screen for opioids; recent drug or alcohol abuseor dependence, with the exception of nicotine dependence, within 6months prior to the identification; history of seizures, includingfebrile seizures, cranial trauma, or other conditions that predisposethe subject to seizures; history of mania or current diagnosis of activepsychosis, active bulimia or anorexia nervosa, but not binge eatingdisorder; a risk for suicide attempts; acute depressive illnessincluding new onset of depression or acute exacerbation of symptoms, butnot stable subjects on chronic treatment for depression; any conditionwith life expectancy anticipated to be less than 4 years includingcongestive heart failure NYHA Class 3 or 4; a history of malignancywithin the previous 5 years, not including non-melanoma skin cancer orsurgically cured cervical cancer; current use of other bupropion ornaltrexone containing products; a history of hypersensitivity orintolerance to naltrexone or bupropion; use of monoamine oxidaseinhibitors within 14 days prior to the identification; use of anyinvestigational drug, device, or procedure within 30 days prior to theidentification; a pregnant or breast-feeding woman, or currently tryingto become pregnant, or of child-bearing potential, includingperi-menopausal women who have had a menstrual period within one year,and not willing to practice birth control; and inability to consistentlyaccess broadband internet.

In some embodiments, the method further comprises providing the subjectwith a web-based weight management program, a phone-based weightmanagement program, or a combination thereof.

An embodiment of the invention includes a method of treating a subjectfor overweight or obesity comprising: identifying an overweight or obesesubject; and administering to the subject a therapeutically effectiveamount of sustained release naltrexone, or a pharmaceutically acceptablesalt thereof, and sustained release bupropion, or a pharmaceuticallyacceptable salt thereof, in combination with a web-based weightmanagement program, a phone-based weight management program, or acombination thereof.

In some embodiments, the identified subject has a BMI ≥30 and ≤45 kg/m²with uncomplicated obesity. In some embodiments, the identified subjecthas a BMI of ≥27 and ≤45 kg/m² with dyslipidemia and/or controlledhypertension. In some embodiments, the subject is treated for at least26 weeks. In some embodiments, the phone-based weight management programcomprise one or more coaching calls to the subject. In some embodiments,the phone-based weight management program optionally comprises one ormore web coaching tools. In some embodiments, the web-based orphone-based weight management program provides the subject with one ormore of behavioral, nutritional or fitness education.

In some embodiments, the education are delivered by a trained health orfitness coach and/or a registered dietitian. In some embodiments, thetrained health or fitness coach and/or the registered dietitian counselthe subject via the phone or via a website for the subject, and provideone or more of the topics selected from the group consisting of tips andmotivational messages; coaching through question and answer; weeklyoffice hours for real-time responses to the subject's inquiries via thewebsite; weekly educational materials; video lessons; weight, exercise,or diet tracking with badge rewards; goal setting; progress tracking;and communications to encourage the subject to engage in the weightmanagement program.

In some embodiments, 32 mg per day of sustained release naltrexone, or apharmaceutically acceptable salt thereof, and 360 mg per day ofsustained release bupropion, or a pharmaceutically acceptable saltthereof, is administered to the subject. In some embodiments, thesubject is administered the sustained release naltrexone, or apharmaceutically acceptable salt thereof, and the sustained releasebupropion, or a pharmaceutically acceptable salt thereof, in a tabletcontaining 8 mg of sustained release naltrexone and 90 mg of sustainedrelease bupropion.

In some embodiments, the treatment with naltrexone and bupropion doesnot increase the subject's risk of an adverse cardiovascular outcome. Insome embodiments, the treatment with naltrexone and bupropion decreasesthe subject's risk of an adverse cardiovascular outcome. In someembodiments, the adverse cardiovascular outcome is cardiovascular death,nonfatal myocardial infarction, or nonfatal stroke. In some embodiments,the subject achieves a percentage of weight loss of at least 5%, atleast 10% or at least 15%. In some embodiments, the weight managementprogram has a period of at least 52 weeks or at least 78 weeks.

In some embodiments, the subject does not receive in-person counselingas part of a weight management program. In some embodiments, the subjectdoes not receive more than 5 in-person counseling sessions as part of aweight management program. In some embodiments, the subject does notreceive an intensive behavioral modification (BMOD) program for weightloss.

BRIEF DESCRIPTION OF THE DRAWINGS

So that the manner in which the recited features of the presentdisclosure can be understood in detail, a more particular description ofthe disclosure, briefly summarized above, may be had by reference toembodiments, some of which are illustrated in the appended drawings. Itis to be noted, however, that the appended drawings illustrate onlytypical embodiments of this disclosure and are therefore not to beconsidered limiting of its scope, for the disclosure may admit to otherequally effective embodiments.

FIG. 1 shows a visual representation of a study design demonstratingthat treatment with Naltrexone SR/Bupropion SR does not increase ordecreases the occurrence of Major Adverse Cardiovascular Events (MACE)in overweight and obese subjects with cardiovascular risk factors aspresented in Example 1; and

FIG. 2 shows a visual representation of a study design demonstrating thebeneficial effect of Naltrexone SR/Bupropion SR on body weight andcardiovascular risk factors in overweight and obese subjects inconjunction with a comprehensive lifestyle intervention (CLI) programcompared minimal lifestyle intervention program as presented in Example2.

DETAILED DESCRIPTION

The present disclosure relates to compositions, kits, uses, systems andmethods for treating overweight and obesity using naltrexone plusbupropion, preferably in combination with a comprehensive lifestyleintervention (CLI) program including a web-based weight managementprogram, a phone-based weight management program, and a combinationthereof. In some embodiments, the subject being treated for overweightand obesity are subjects at increased risk of adverse cardiovascularoutcomes. In a preferred embodiment, the treatment of a subject atincreased risk of adverse cardiovascular outcomes with naltrexone plusbupropion in combination with a comprehensive web-based and/ortelephone-based weight management program results in no more majoradverse cardiovascular outcomes than treatment with the web-based and/ortelephone-based weight management program alone. In some embodiments,the treatment of a subject at increased risk of adverse cardiovascularoutcomes with naltrexone plus bupropion in combination with acomprehensive web-based and/or telephone-based weight management programsurprisingly results in fewer major adverse cardiovascular outcomes thantreatment with the web-based and/or telephone-based weight managementprogram alone. Major adverse cardiovascular outcomes are cardiovasculardeath (including fatal myocardial infarction and fatal stroke), nonfatalmyocardial infarction, nonfatal stroke, or nonfatal unstable anginarequiring hospitalization.

In some embodiments, the subject being treated by the methods disclosedherein is at increased risk of adverse cardiovascular outcomes. Subjectsat increased risk of adverse cardiovascular outcomes include subjectshaving a.) cardiovascular disease (confirmed diagnosis or at highlikelihood of cardiovascular disease) with at least one of thefollowing: history of documented myocardial infarction >3 months priorto screening; history of coronary revascularization (i.e., coronaryartery bypass graft surgery, stent placement, percutaneous transluminalcoronary angioplasty, or laser atherectomy); history of carotid orperipheral revascularization (i.e., carotid endarterectomy, lowerextremity atherosclerotic disease atherectomy, repair of abdominal aortaaneurysm, femoral or popliteal bypass); angina with ischemic changes(resting ECG), ECG changes on a graded exercise test (GXT), or positivecardiac imaging study; ankle brachial index <0.9 (by simple palpation)within prior 2 years; ≥50% stenosis of a coronary, carotid, or lowerextremity artery within prior 2 years; and/or b. Type 2 diabetesmellitus with at least 2 of the following: hypertension (controlled withor without pharmacotherapy at <145/95 mm Hg); dyslipidemia requiringpharmacotherapy; documented low HDL cholesterol (<50 mg/dL in women or<40 mg/dL in men) within prior 12 months; current tobacco smoker.

In some such embodiments, the subject being treated has uncomplicatedobesity. In some other embodiments, the subject being treated isoverweight and has dyslipidemia and/or controlled hypertension. In someembodiments, the subject being treated by the methods disclosed hereinis not at increased risk of adverse cardiovascular outcomes.

In some embodiments the treatment with naltrexone and bupropion iscombined with a weight management program. In some embodiments, theweight management program is a web-based program. In some otherembodiments, the weight management program is a phone-based program. Insome other embodiments, the weight management program is a combinationof both web-based and phone-based programs. In some embodiments, thesubject does not receive more than 15, 10, 5, 4, 3, 2, or 1 in-personcounseling sessions as part of a weight management program. In someembodiments, the subject does not receive any in-person counselingsessions as part of a weight management program.

Web-Based Weight Management Program

Preferably, the web-based program provides a progressive nutrition andexercise program with goal setting and tracking tools. Each subject isassigned to a health and fitness professional who counsels them onlinethroughout the program. Additional educational tools include weeklyweb-based informational, educational and motivational resourcessupplemented by video lessons (Table 1) presented at regular intervals.Content for the program consists of: a weekly email that announces thegoals for the week, provides motivation, and encourages continuedparticipation; weekly goals (from email) that align with each week'stheme (Table 1), along with a detailed explanation and a strategy forachieving these goals, placed on the MyWeightMate.com subject pages;three pieces of additional weekly content posted to user pages (tips andeducational information) to help subjects reach their weekly goals;motivational messages throughout the week posted on participant pages;triggered event emails sent to users based on behaviors (i.e. absencefrom program activity, successful logging); video lessons provided onthe MyWeightMate.com site for participants to view and archived forfuture access: weekly for the first 16 weeks, biweekly for the next 12weeks, monthly for the remaining duration of the study, and tworefresher campaigns that include 4 weekly sessions each year during thethird and fourth year of the trial. Video lessons focus on relevanttopics and are developed by subject matter experts.

TABLE 1 Weekly Themes and Video Topics for First 16 Weeks of the WeightManagement Program Week Theme Video Lesson Topic 1 Get Started SettingYourself Up For Success: Getting Your Mind Right 2 Perfect PortionsSMART Goals 3 Avoid Pitfalls Proper Form When You Move 4 Get MoreVitamin Zzz Healthful Substitutions for Food and Exercise 5 Boost YourFitness Fitness Myths 6 Skinny Food Secrets Smart Strategies for EatingLess 7 Smash Sugar Spikes How Do You Make Time For Your Health and Whyis It Psychologically Important? 8 Take the Show on the Road AccidentalExercise 9 Take Some Pressure Off Powering Up Your Exercise 10Metabolism Superchargers Staying Fit If You Sit 11 Clobber HighCholesterol Healthy Choices 12 Motivation Boosters Breaking Weight LossPlateaus 13 Kick It Up Replacing Bad Habits With Healthy Ones 14 RutBusters The Diet Hype Trap 15 Shore Up Your Self- Healthy Living Guide:Live Confidence Your Best Life 16 Review and Renew Boost Your Metabolism

The web-based weight management program provides behavioral, nutritionaland fitness education delivered by trained health and fitness coaches.The website provides a “WeightMate Coach” who counsels the subject viathe participant's individual webpage, and provides one or more of thefollowing: tips and motivational messages; coaching through Q&A; weeklyoffice hours for real-time response via the website; weekly educationalmaterials; content developed with subject matter experts; video lessonsto supplement the weekly themes; weight, exercise, and diet trackingwith badge rewards; suggested activity and coaching tip; communicationto encourage engagement; and a contemporary website that is fun andintuitive.

In one embodiment, new themes and goals are introduced each Monday, with2-3 goals of the week, relevant content and/or video lesson(s) (Table 1)are provided, and motivational messages are provided on one or more daysof the week. Optionally, additional tips are provided one or more daysduring the week. In some embodiments, video lessons supplement theweekly educational themes. The produced video content ensures qualityand uniformity of message to subjects, and a Q&A function allowspatients to ask questions with <24 hour turnaround.

In some embodiments, web-based individual counseling is provided by acoach; preferably the subject has unlimited access to coach. Preferablythe coach provides a schedule to the subject which includes weekly‘office hours’ for real-time Q&A responses. The program emphasizesweekly weigh ins with daily food and activity tracking. Preferably, thewebsite can track calories for each meal using a computer database ofcalories for specific foods and/or meals, and save favorite foods andmeals. Four reference menus based on caloric needs and food preferencesare provided. In some embodiments the subject is rewarded with badgesfor meeting particular goals (e.g., for 7 days of activity logged; for 7days of food logged; for 3 weeks of weight logged; for first 15 poundslost; for 12 weeks of program participation; for 26 weeks of programparticipation; for 52 weeks of program participation; for 78 weeks ofprogram participation; for 5% weight loss; for 10% weight loss; for 15%weight loss). In a preferred embodiment, the subject periodicallyestablishes a weight loss goal which is recorded as part of the program.The subject's progress toward the subject's goal(s) can be provided tothe subject via the subject's webpage. The weight loss goal can be thegoal for a one week, two week, month, two month, six month, year orlonger period of time. The program provides the option for theparticipating subject to set a specific weight loss goal at thebeginning of the program. The program also provides the option to trackand log weight loss, and the progress towards achieving the specificgoal on a daily or weekly basis. Optionally, a graphic representation ofweight loss progress is provided to the subject via the subject'swebpage. Periodic encouraging messages (e.g., badges and award notes)can be provided. Preferably, behavior-based automated messages fromtrainers are provided for increased motivation and participation.

In some embodiments, the exercise portion of the web-based weightmanagement program encourages 5 days of activity and 2 days of rest,preferably on nonconsecutive days (e.g. Monday and Friday). In someembodiments, the exercise program provides instructions on stretching,walking and other light cardio activity. Video clips can provideeducational demonstration for stretches and exercise maneuvers. Thewebsite can track calories burned by the subject through exercise andactivity logs.

In a preferred embodiment, the web-based weight management program doesnot involve any in-person therapy or group meetings.

Phone-Based Weight Management Program

In some embodiments, the telephone-based program comprises personalizedcoaching through one or more phone calls. In one embodiment, the phonecalls are conducted by a dedicated coach to the subject receivingtreatment. In another embodiment, the phone calls are conducted by aregistered dietitian to the subject receiving treatment. In some suchembodiments, the phone-based program includes 6 to 15, preferably 12scheduled calls over the first 3 to 8, preferably 6 months of thetreatment. The topics of said scheduled calls can include cognitivebehavioral coaching and nutrition coaching (See, for example, Table 2).In some such embodiments, the phone-based program includes 6 to 15,preferably 12 additional calls over the next 3 to 8, preferably 6 monthsof treatment.

In some embodiments, the phone-based program optionally compriseson-line coaching tools, such as an integrated web support for webcoaching, including the web-based program described above. The webcoaching can include the essential practices for weight loss andmaintaining weight loss, progress tracking, and/or virtual coaching.Non-limiting examples of the essential practices can include E-lessons,videos and podcasts, articles and games relating to topics such ashealthy cooking, setting realistic goals, and controlling stress.Non-limiting examples of items the progress trackers can track includeweight, nutrition intake, activity, stress, biometrics, coaching calls,etc. Non-limiting example of virtual coating can include generating andupdating of to-do list for a subject participating in the program,sending emails, etc.

In some embodiments, the phone-based program can also optionally includeone or more electronic devices for wireless activity monitoring.Non-limiting example of such electronic device is FitLinxx®ActiPed to beused in conjunction with a USB access point to track steps, distance,calories and activity time. The electronic device(s) can be wirelesslysynced with the web support. In one embodiment, the phone-based programis the Weight Talk® Program available from Alere™.

A subject receiving the treatment of naltrexone and bupropion can enrollin the phone-based program via various methods, including both webenrollment and phone enrollment. In some embodiments, the phone-basedprogram also include frontline support to identify patients who qualifyfor the clinical study, discuss benefit of the phone-based program, setrealistic expectations, assist in enrollment and refer specific questionto coaches.

TABLE 2 Exemplary Phone-based Weight Management Program Call Topics Call# Call Topics Call 1: Getting Started: Core Values, goal setting andtracking Call 2: Reducing calories and healthy eating (with registereddietitian) Call 3: Increasing physical activity Call 4: Managing stressCall 5: Changing unhelpful thoughts Call 6: Gaining control of yourenvironment (with registered dietitian) Call 7: Developing timemanagement skills and improving sleep Call 8: Navigating difficultsituations: social situations and restaurants Call 9: Weight maintenanceskills Call 10: Rebounding from lapses Call 11: Maintaining motivationCall 12: Evaluation and Participant Feedback

In a preferred embodiment, treatment with a combination of naltrexonesustained-release (SR)/bupropion SR (NB), alone or in conjunction with aweb-based and/or telephone-based weight management program, does notincrease, or more preferably decreases, the occurrence of major adversecardiac events, defined as cardiovascular death, nonfatal myocardialinfarction, or nonfatal stroke in overweight and obese subjects, ascompared to placebo or a web-based and/or telephone-based weightmanagement program alone. In some embodiments, treatment with NB, aloneor in conjunction with a web-based and/or telephone-based weightmanagement program, does not increase, or more preferably decreases, theoccurrence of one or more of cardiovascular death, nonfatal myocardialinfarction, nonfatal stroke, or nonfatal unstable angina requiringhospitalization in overweight and obese subjects, as compared to placeboor a web-based and/or telephone-based weight management program alone.In some embodiments, treatment with NB, alone or in conjunction with aweb-based and/or telephone-based weight management program, does notincrease, or more preferably decreases, one or more of: the occurrenceof all cause mortality; the occurrence of unstable angina requiringhospitalization; and the occurrence of coronary revascularizationprocedures, as compared to placebo or a web-based and/or telephone-basedweight management program alone. In some embodiments, treatment with NB,alone or in conjunction with a web-based and/or telephone-based weightmanagement program, decreases body weight or improves systolic and/ordiastolic blood pressure, as compared to placebo or a web-based and/ortelephone-based weight management program alone. In some embodiments,the individual treated is overweight or obese, and at increased risk ofadverse cardiovascular outcomes.

In some embodiments, treatment with a combination of naltrexonesustained-release (SR)/bupropion SR (NB), alone or in conjunction with aweb-based and/or telephone-based weight management program, increasesone or more of: the percent change in body weight from baseline; thepercentage of subjects achieving a loss of at least 5%, 10%, and 15% ofbaseline body weight; and the absolute change in body weight frombaseline, compared to Usual Care (no study medication and minimallifestyle intervention program). In some embodiments, treatment with NB,alone or in conjunction with a web-based and/or telephone-based weightmanagement program, improves one or more of: cardiovascular risk factors(one or more of waist circumference, fasting triglycerides, fasting LDLcholesterol, and fasting HDL cholesterol); vital signs (one or more ofsystolic and/or diastolic blood pressure, and heart rate); measures ofglucose metabolism (one or more of fasting glucose, fasting insulin, andHOMAIR); measurements derived from patient reported outcomes (one ormore of eating behavior (e.g. BES), sexual function (e.g. ASEX Scale),and weight-related quality of life (e.g. IWQOL-Lite)), as compared toUsual Care (no study medication and minimal lifestyle interventionprogram). In some embodiments, the above mentioned increases orimprovements are measured at week 26 of treatment in comparison tobaseline, in some embodiments the measurements are at week 52 or 78 oftreatment in comparison to baseline. In some embodiments that treatedindividual is female or male, 18 to 60 years, inclusive, of age, with aBMI ≥30 and ≤45 kg/m² for subjects with uncomplicated obesity, and a BMIof ≥27 and ≤45 kg/m² for subjects who are overweight or obese and havedyslipidemia and/or controlled hypertension. In some embodiments thetreated individual is overweight or obese, and at increased risk ofadverse cardiovascular outcomes. In some embodiments, the treatedindividual is not overweight or obese, and at increased risk of adversecardiovascular outcomes.

In some embodiments, treatment with a combination of naltrexonesustained-release (SR)/bupropion SR (NB), in conjunction with aweb-based and/or telephone-based weight management program, is the sameor increases one or more of: the percent change in body weight frombaseline; the percentage of subjects achieving a loss of at least 5%,10%, and 15% of baseline body weight; and the absolute change in bodyweight from baseline, compared to NB in conjunction with an intensivebehavioral modification (BMOD) program for weight loss delivered inperson. In some embodiments, treatment with NB, alone or in conjunctionwith a web-based and/or telephone-based weight management program, isthe same or improves one or more of: cardiovascular risk factors (one ormore of waist circumference, fasting triglycerides, fasting LDLcholesterol, and fasting HDL cholesterol); vital signs (one or more ofsystolic and/or diastolic blood pressure, and heart rate); measures ofglucose metabolism (one or more of fasting glucose, fasting insulin, andHOMA-IR); measurements derived from patient reported outcomes (one ormore of eating behavior (e.g. BES), sexual function (e.g. ASEX Scale),and weight-related quality of life (e.g. IWQOL-Lite)), as compared to NBin conjunction with an intensive behavioral modification (BMOD) programfor weight loss delivered in person. In some embodiments, the abovementioned increases or improvements are measured at week 26 of treatmentin comparison to baseline, in some embodiments the measurements are atweek 52 or 78 of treatment in comparison to baseline. In someembodiments that treated individual is female or male, 18 to 60 years,inclusive, of age, with a BMI ≥30 and ≤45 kg/m² for subjects withuncomplicated obesity, and a BMI of ≥27 and ≤45 kg/m² for subjects whoare overweight or obese and have dyslipidemia and/or controlledhypertension. In some embodiments the treated individual is overweightor obese, and at increased risk of adverse cardiovascular outcomes. Insome embodiments, the treated individual is not overweight or obese, andat increased risk of adverse cardiovascular outcomes.

In some embodiments, the individual has a body mass index (BMI) of atleast 25 kg/m². In some embodiments, the individual has a BMI of atleast 30 kg/m². In some embodiments, the individual has a BMI of atleast 40 kg/m². In some embodiments, the individual has a BMI of lessthan 25 kg/m², or develops a BMI less than 25 kg/m² during the course ofadministration of naltrexone and bupropion. In these embodiments, it maybe beneficial for health or cosmetic purposes to mitigate subsequentweight gain or to promote weight loss, thereby reducing the BMI evenfurther. In some embodiments, the individual has been diagnosed by aphysician as being overweight or obese. In some embodiments, theindividual is identified, including self-identified, as overweight orobese, or is identified as having been diagnosed as overweight or obese.In some embodiments, the individual is suffering from dyslipidemiaand/or controlled hypertension in addition to being overweight, or inaddition to being obese.

In some embodiments, the promotion of weight loss is measured by apercent change from a baseline body weight. In some of theseembodiments, the amount of weight loss is, is about, is at least, is atleast about 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%,12%, 15%, or more of initial body weight, or a range defined by any twoof the preceding values. In some embodiments, the promotion of weightloss is measured as a reduction in weight gain relative to the amount ofweight gain experienced by the relevant control, and the amount ofreduction in weight gain is, is about, is at least, is at least about,2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%,105%, 110%, 115%, 120%, or more, or a range defined by any two of thepreceding values.

In some embodiments, the dosage is adjusted so that the patient losesweight at a rate of about 3% of baseline body weight every six months.However, the rate of weight loss for a patient may be adjusted by thetreating physician based on the patient's particular needs.

In some embodiments, the mitigation of weight gain or promotion ofweight loss occurs by increasing satiety in the individual. In someembodiments, the mitigation of weight gain or promotion of weight lossoccurs by suppressing the appetite of the individual. In someembodiments, the treatment comprises instituting a regimen of dietand/or increased activity.

In some embodiments, the naltrexone or combination therapy, includingnaltrexone in combination with bupropion or fluoxetine, is in an amountsufficient to affect weight loss, reduce a cardiovascular risk factor,increase insulin sensitivity, reduce food cravings, treat a visceral fatcondition, mitigate weight gain or promote weight loss during smokingcessation, or provide weight loss therapy in patients with majordepression. Nonlimiting examples of such methods of treatment aredisclosed in U.S. Pat. Nos. 7,375,111 and 7,462,626; in U.S. PatentPublication Nos. 2007/0275970, 2007/0270450, 2007/0117827, 2007/0179168,2008/0214592, 2007/0128298, and 2007/0129283; in U.S. patent applicationSer. Nos. 12/751,970, 61/167,486, and 61/293,844; and in WO 2009/158114,each of which is hereby incorporated herein by reference in theirentirety and for all purposes, including without limitation for thepurpose of describing methods of affecting weight loss, reducingcardiovascular risk factors, increasing insulin sensitivity, reducingfood cravings, treating visceral fat conditions, mitigating weight gainor promoting weight loss during smoking cessation, and providing weightloss therapy in patients with major depression. In some embodiments, thecardiovascular risk factor includes one or more of the following: totalcholesterol level, LDL cholesterol level, HDL cholesterol level,triglyceride level, glucose level, and insulin level. In someembodiments, the cardiovascular risk factor includes one or more of thefollowing: total cholesterol level, HDL cholesterol level, andtriglyceride level.

In some embodiments, the increased efficacy of a weight loss treatmentdescribed herein comprises an improvement in an outcome measure. Forexample, in some embodiments, the increased efficacy increases theamount of weight loss. In some embodiments, the increase in efficacydecreases the frequency or severity of adverse events, including but notlimited to nausea, constipation, vomiting, dizziness, dry mouth,headache, and insomnia. In some embodiments, the increased efficacyimproves another secondary endpoint, including but not limited to waistcircumference, high-sensitivity C-reactive protein (hs-CRP) levels,triglyceride levels, HDL cholesterol levels or the ratio of LDL/HDLcholesterol levels. As one of skill in the art recognizes, in somecircumstances, it is desirable to decrease waist circumference, hs-CRPlevels, triglyceride levels, and the ratio of LDL/HDL cholesterollevels, and to increase HDL cholesterol levels. In some embodiments, theimprovement in the outcome measure is, is about, is at least, or is atleast about 1, 2, 3, 4, 5, 7, 10, 12, 15, 20 30, 40, 50, 60, 70, 80, 90,or 100%, or within a range defined by any two of these values ascompared to baseline or the relevant control.

In some embodiments, naltrexone or naltrexone and bupropion are eachadministered once per day. In some embodiments, naltrexone and bupropionare each divided into equal doses and administered more than once perday. In some embodiments, naltrexone and bupropion are each divided intounequal doses and administered more than once per day. In someembodiments, naltrexone and bupropion are divided into a differentnumber of doses and are administered a different number of times perday. In one such embodiment, the dose of one of naltrexone or bupropionis divided, while the dose of the other is not.

In some embodiments, one or both of naltrexone and bupropion isadministered one, two, three, four, or more times per day. Either orboth compounds can be administered less than once per day, for exampleonce every 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days, or every1 or 2 weeks, or a range defined by any two of the preceding values. Insome embodiments, the number of administrations per day is constant(e.g., one time per day). In other embodiments, the number ofadministrations is variable. The number of administrations may changedepending on effectiveness of the dosage form, observed side effects,external factors (e.g., a change in another medication), or the lengthof time that the dosage form has been administered.

In some embodiments, the daily dose of naltrexone can range from about 4mg to about 50 mg, or about 4 mg to about 32 mg, or about 8 mg to about32 mg, or about 8 mg to about 16 mg. In some embodiments, the daily doseis about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 32 mg, orabout 48 mg of naltrexone, or a range defined by any two of thepreceding values. The selection of a particular dosage may be based onthe weight of the patient. The selection of a particular dosage may bebased on the identity, dosage, and/or dosing schedule of anotherco-administered compound. However, in some embodiments, it may benecessary to use dosages outside these ranges. In some embodiments, thedaily dose is administered in a single oral dosage form. In someembodiments, the daily dose of naltrexone is the same, and in someembodiments, the daily dose is different.

In some embodiments, the daily dose of bupropion can range from about 30mg to about 500 mg, or about 30 mg to about 360 mg, or about 90 mg toabout 360 mg. In some embodiments, the daily dose is about 30 mg, about90 mg, about 180 mg, about 360 mg, or about 450 mg of bupropion, or arange defined by any two of the preceding values. The selection of aparticular dosage may be based on the weight of the patient. Theselection of a particular dosage may be based on the identity, dosageand/or dosing schedule of another co-administered compound. However, insome embodiments, it may be necessary to use dosages outside theseranges. In some embodiments, the daily dose is administered in a singleoral dosage form. In some embodiments, the daily dose of bupropion isthe same, and in some embodiments, the daily dose is different.

The compositions described herein may be distributed, provided to apatient for self-administration, or administered to an individual. Insome embodiments, the combined naltrexone/bupropion therapies include athird compound.

In some embodiments, naltrexone and/or bupropion are provided oradministered as an oral dosage form. In some embodiments, the oraldosage form is in the form of a pill, tablet, core, capsule, caplet,loose powder, solution, or suspension. In a preferred embodiment, theoral dosage form is in the form of a pill, tablet, or capsule. In someembodiments, the combined naltrexone/bupropion therapy is provided in asingle oral dosage form. In some embodiments, the oral dosage form is inthe form of a trilayer tablet as described in U.S. Patent PublicationNo. 2008/0113026, which is incorporated herein by reference in itsentirety and for all purposes, including without limitation for thepurpose of describing trilayer tablets, methods of making andformulating trilayer tablets, and methods of administering them.

In some embodiments, at least one of naltrexone and bupropion isadministered with varying frequency during treatment. In some of theseembodiments, the varying frequency comprises a decreased frequency overtime. For example, one or both of naltrexone and bupropion can beinitially administered more than once per day, followed byadministration only once per day at a later point in treatment. In someembodiments, the daily dosage of at least one of naltrexone andbupropion is consistent despite the varying frequency of administration.For example, in some embodiments, two tablets of each of naltrexone andbupropion are initially administered twice per day, while four tabletsof each of naltrexone and bupropion are administered once per day at alater point in treatment. Alternatively, in some embodiments, one or twotablets of each of naltrexone and bupropion are administered at a laterpoint in treatment, where the one or two tablets have an equivalenttotal daily dosage as the two tablets each of naltrexone and bupropioninitially administered twice per day.

In some embodiments where one or both of naltrexone and bupropion areadministered less than once per day in a controlled release or sustainedrelease (SR) formulation, the dose is selected so that the patientreceives a daily dose that is about the same as a daily dose describedherein.

In some embodiments, the naltrexone, alone or in a combinationtreatment, is not a sequestered form of naltrexone. For example, in someembodiments, naltrexone is in a non-sequestered, controlled releaseformulation. In some embodiments, naltrexone is a non-sequestered,sustained release formulation. In preferred embodiments, at least 50% ofthe naltrexone is released within 24 hours of administration.

In some embodiments, at least one of naltrexone or bupropion isadministered in consistent daily dosages throughout the period oftreatment. In some embodiments, at least one of naltrexone or bupropionis administered in varying daily dosages during the period of treatment.In some of these embodiments, the daily dosages comprise increasingdaily dosages over time. In some of these embodiments, the daily dosagescomprise decreasing daily dosages over time.

In some embodiments, naltrexone and bupropion are administeredindividually. In some embodiments, naltrexone and bupropion areadministered in a single pharmaceutical composition comprisingnaltrexone and bupropion. In some embodiments, at least one ofnaltrexone or bupropion is in a sustained release or controlled releaseformulation. For example, sustained release forms of naltrexone aredescribed in U.S. Patent Publication No. 2007/0281021, which isincorporated herein by reference in its entirety and for all purposes,including without limitation for the purpose of describing sustainedrelease forms of naltrexone and bupropion, methods of making andformulating them into suitable dosage forms, and methods ofadministering them. In some embodiments, at least one of naltrexone orbupropion is administered with a physiologically acceptable carrier,diluent, or excipient, or a combination thereof. Non-limiting examplesof naltrexone/bupropion combinations, formulations thereof, and methodsof administering them are disclosed in U.S. Pat. Nos. 7,375,111 and7,462,626, both of which are incorporated herein by reference in theirentirety and for all purposes, including without limitation for thepurpose of describing combinations of naltrexone and bupropion, methodsof making and formulating them into suitable dosage forms, and methodsof administering them. Reference herein to the use or administration ofnaltrexone and naltrexone/bupropion combinations is understood toinclude all modes of administration disclosed or referred to herein,including without limitation separate administration, administration ina single dosage form, administration in the form of salts, and/ormetabolites, and/or administration in sustained release forms.Techniques for formulation and administration of the compounds of theinstant application may be found in “Remington's PharmaceuticalSciences,” Mack Publishing Co., Easton, Pa., 18th edition, 1990, whichis incorporated herein by reference in its entirety.

In some embodiments, naltrexone is administered prior to bupropion. Insome embodiments, naltrexone is administered subsequent to bupropion. Insome embodiments, naltrexone and bupropion are co-administered. As usedherein, co-administration includes administration in a single dosageform, or separate dosage forms that are administered at, or nearly at,the same time.

In some embodiments, the administration of naltrexone and bupropion iscontinued for a period of, or of about, 1, 2, 3, 4, 6, 8, 10, 12, 16,20, 24, 36, 48, or 52 weeks, or a range defined by any two of thepreceding values. In some embodiments, the administration of naltrexoneand bupropion is continued until the reduction in symptoms of a disease,disorder, or condition is stabilized for a period of, or of about, 1, 2,3, 4, 5, 6, or more weeks, or a range defined by any two of thepreceding values. For example, in some embodiments, the administrationof a combined naltrexone/bupropion therapy is continued until themitigation of weight gain or promotion of weight loss in an individualis stabilized for a period of, or of about, 1, 2, 3, 4, 5, 6, or moreweeks, or a range defined by any two of the preceding values. In someembodiments, administration of naltrexone, or naltrexone and bupropion,is continued until the individual no longer needs a treatment.

In some embodiments, “administering” a drug includes an individualobtaining and taking a drug on their own. For example, in someembodiments, an individual obtains a drug from a pharmacy andself-administers the drug in accordance with the methods providedherein.

In some embodiments, the present invention relates to a kit. The kit mayinclude one or more unit dosage forms comprising naltrexone, bupropion,or naltrexone and bupropion. The unit dosage forms may be of an oralformulation. For example, the unit dosage forms may comprise pills,tablets, or capsules. The kit may include a plurality of unit dosageforms. In some embodiments, the unit dosage forms are in a container. Insome embodiments, the dosage forms are single oral dosage formscomprising naltrexone and bupropion or pharmaceutically acceptable saltsthereof.

The methods, compositions and kits disclosed herein may includeinformation. The information may be in a form prescribed by agovernmental agency regulating the manufacture, use, or sale ofpharmaceuticals, which notice is reflective of approval by the agency ofthe form of the drug for human or veterinary administration. Suchinformation, for example, may be the labeling approved by the U.S. Foodand Drug Administration for prescription drugs, or the approved productinsert. The information can include required information regarding doseand dosage forms, administration schedules and routes of administration,adverse events, contraindications, warning and precautions, druginteractions, and use in specific populations (see, e.g., 21 C.F.R. §201.57 which is incorporated herein by reference in its entirety), andin some embodiments is required to be present on or associated with thedrug for sale of the drug. Dosage forms comprising a sustained-releasenaltrexone formulation of the invention formulated in a compatiblepharmaceutical carrier may also be prepared, placed in an appropriatecontainer, and labeled for treatment of an indicated condition. In someembodiments, a kit is for sale of a prescription drug requiring theapproval of and subject to the regulations of a governmental agency,such as the Food and Drug Administration of the United States. In someembodiments, the kit comprises the label or product insert required bythe agency, such as the FDA, for sale of the kit to consumers, forexample in the U.S.

The information may comprise instructions to administer the unit dosageform at a dosage of about 4 mg, about 8 mg, about 12 mg, about 16 mg,about 32 mg, or about 48 mg of naltrexone or a pharmaceuticallyacceptable salt thereof. The information may comprise instructions toadminister the unit dosage form at a dosage of about 30 mg, about 90 mg,about 180 mg, about 360 mg, or about 450 mg of bupropion or apharmaceutically acceptable salt thereof. These instructions may beprovided in a variety of ways. The information may comprise instructionsabout when to administer the unit dosage forms. For example, theinformation may comprise instructions about when to administer the unitdosage forms relative to the administration of another medication orfood. In preferred embodiments, the information instructs an individualto take naltrexone, or naltrexone and bupropion, with food, preferably ameal.

Some embodiments include information, preferably printed, that takingnaltrexone or a pharmaceutically acceptable salt thereof with foodresults in an increase in the bioavailability of naltrexone or apharmaceutically acceptable salt thereof compared to taking the sameamount of naltrexone or a pharmaceutically acceptable salt thereofwithout food. Some embodiments include information, preferably printed,that taking bupropion or a pharmaceutically acceptable salt thereof withfood results in an increase in the bioavailability of bupropion or apharmaceutically acceptable salt thereof compared to taking the sameamount of bupropion or a pharmaceutically acceptable salt thereofwithout food. Some embodiments include information, preferably printed,that taking naltrexone and bupropion, or a pharmaceutically acceptablesalts thereof, with food results in an increase in the bioavailabilityof naltrexone and/or bupropion, or a pharmaceutically acceptable saltsthereof, compared to taking the same amount of naltrexone and bupropion,or a pharmaceutically acceptable salts thereof, without food. Someembodiments include information, preferably printed, that takingnaltrexone, and/or bupropion or pharmaceutically acceptable saltsthereof with food results in fewer or less severe drug associatedadverse events than taking the same amount of naltrexone and bupropion,or a pharmaceutically acceptable salts thereof, without food. In someembodiments, the adverse events are gastrointestinal events. In someembodiments, information regarding bioavailability, adverse events, orinstructions on administration regimes are provided to a subject, adosage form comprising the medication described in the information isprovided to the subject, and the dosage form is administered inaccordance to the information. In some embodiments the subject is apatient in need of the medication. In some embodiments the medication isadministered as a therapy for a disease as described herein.

In some embodiments, the methods, compositions and kits disclosed hereinmay include information regarding enrolling and/or accessing a web-basedand/or telephone-based weight management program. In some embodiments,the enrollment in a web-based and/or telephone-based weight managementprogram is a requirement of obtaining the treatment medication. In someembodiments, the enrollment in a web-based and/or telephone-based weightmanagement program is permitted only after obtaining a prescription forthe treatment medication or the actual medication. In some embodiments,the method of treatment comprises enrolling in a web-based and/ortelephone-based weight management program prior to and/or as a conditionof receiving the treatment medication. In some embodiments, theinformation includes a unique login or enrollment key for enrollingand/or accessing a web-based and/or telephone-based weight managementprogram.

Instructions and/or information may be present in a variety of forms,including printed information on a suitable medium or substrate (e.g., apiece or pieces of paper on which the information is printed), computerreadable medium (e.g., diskette, CD, etc. on which the information hasbeen recorded), or a website address that may be accessed via theinternet. Printed information may, for example, be provided on a labelassociated with a drug product, on the container for a drug product,packaged with a drug product, or separately given to the patient apartfrom a drug product, or provided in manner that the patient canindependently obtain the information (e.g., a website). Printedinformation may also be provided to a medical caregiver involved intreatment of the patient. In some embodiments, the information isprovided to a person orally.

Some embodiments comprise a therapeutic package suitable for commercialsale. Some embodiments comprise a container. The container can be in anyconventional shape or form as known in the art which is made of apharmaceutically acceptable material, for example a paper or cardboardbox, a glass or plastic bottle or jar, a re-sealable bag (e.g., to holda “refill” of tablets for placement into a different container), or ablister pack with individual dosages for pressing out of the packaccording to a therapeutic schedule. The container employed can dependon the exact dosage form involved, e.g., a conventional cardboard boxwould not generally be used to hold a liquid suspension. It is feasiblethat more than one container can be used together in a single package tomarket a single dosage form. For example, tablets may be contained in abottle which is in turn contained within a box. Non-limiting examples ofpacks and dispensers as well as oral dosage forms are disclosed in U.S.Patent Publication Nos. 2008/0110792 and 2008/0113026, both of which arehereby incorporated herein by reference in their entirety and for allpurposes, including without limitation for the purpose of describingcombinations of naltrexone and bupropion, methods of making andformulating them into suitable dosage forms, methods of packing anddispensing them, and methods of administering them.

The information can be associated with the container, for example, bybeing: written on a label (e.g., the prescription label or a separatelabel) adhesively affixed to a bottle containing a dosage form describedherein; included inside a container as a written package insert, such asinside a box which contains unit dose packets; applied directly to thecontainer such as being printed on the wall of a box; or attached as bybeing tied or taped, e.g., as an instructional card affixed to the neckof a bottle via a string, cord or other line, lanyard or tether typedevice. The information may be printed directly on a unit dose pack orblister pack or blister card.

The term “bupropion” may be used in a general way herein to refer to afree base of bupropion, a pharmaceutically acceptable bupropion salt(including anhydrous forms, e.g., anhydrous bupropion), a bupropionmetabolite (e.g., hydroxybupropion, threohydrobupropion, anderythrohydrobupropion), a bupropion isomer, or mixtures thereof.

The term “naltrexone” may be used in a general way herein to refer to afree base of naltrexone, a pharmaceutically acceptable naltrexone salt(including hydrates and anhydrous forms, e.g., naltrexone hydrochloridedihydrate and anhydrous naltrexone hydrochloride), a naltrexonemetabolite, a naltrexone isomer, or mixtures thereof.

The term “pharmaceutically acceptable salt,” as used herein, refers to aformulation of a compound that does not cause significant irritation toan organism to which it is administered and does not abrogate thebiological activity and properties of the compound. Pharmaceutical saltscan be obtained by routine experimentation. Non-limiting examples ofpharmaceutically acceptable salts include bupropion hydrochloride,radafaxine hydrochloride, naltrexone hydrochloride, and 6-β naltrexolhydrochloride.

Throughout the present disclosure, when a particular compound ismentioned by name, for example, bupropion or naltrexone, it isunderstood that the scope of the present disclosure encompassespharmaceutically acceptable salts, esters, amides, or metabolites of thenamed compound. For example, in any of the embodiments herein, an activemetabolite of naltrexone (e.g., 6-β naltrexol) can be used incombination with, or instead of, naltrexone. In any of the embodimentsherein, an active metabolite of bupropion, includingS,S-hydroxybupropion (i.e., radafaxine), can be used in combinationwith, or instead of, bupropion.

The term “sustained release,” as used herein, has its ordinary meaningas understood by those skilled in the art and thus includes, by way ofnon-limiting example, the controlled release of a drug from a dosageform over an extended period of time. For example, in some embodiments,sustained-release dosage forms are those that have a release rate thatis slower that of a comparable immediate release form, e.g., less than80% of the release rate of an immediate-release dosage form.

An immediate-release naltrexone formulation appropriate for use as areference standard is the immediate-release naltrexone formulation,widely available commercially as the REVIA® brand of naltrexonehydrochloride, or an equivalent thereof. An immediate-release bupropionformulation appropriate for use as a reference standard is theimmediate-release bupropion formulation, widely available commerciallyas the WELLBUTRIN® brand of bupropion, or an equivalent thereof. TheU.S. government regulates the manner in which prescription drugs can belabeled and thus reference herein to the REVIA® brand of naltrexonehydrochloride and WELLBUTRIN® brand of bupropion have well-known, fixed,and definite meanings to those skilled in the art.

The term “oral dosage form,” as used herein, has its ordinary meaning asunderstood by those skilled in the art and thus includes, by way ofnon-limiting example, a formulation of a drug or drugs in a formadministrable to a human, including pills, tablets, cores, capsules,caplets, loose powder, solutions, and suspensions.

The terms “mitigate” or “mitigation” of weight gain, as used herein,include preventing or decreasing the amount of weight gain associated,e.g., with the administration of a drug or a change in life activity. Insome embodiments, mitigation of weight gain is measured relative to theamount of weight gain typically experienced when only one or neither ofnaltrexone or bupropion is administered.

The term “promotion” of weight loss, as used herein, includes causingweight loss relative to a baseline weight for a least a portion of theperiod of treatment. This includes an individual that initially gainssome weight, but during the course of treatment loses weight relative toa baseline prior to beginning treatment, as well as individuals thatregain a portion or all of the weight that is lost by the end of thetreatment period. In a preferred embodiment, at the end of the treatmentperiod, the individual has lost weight relative to a baseline. In apreferred embodiment, mitigation of weight gain or promotion of weightloss in a patient administered naltrexone and bupropion is greater thanwhen neither or only one of naltrexone or bupropion is administered, andmore preferably an at least additive, or better than additive, orsynergistic, effect of administering the two compounds is achieved.

In any of the embodiments described herein, methods of treatment canalternatively entail use claims, such as Swiss-type use claims. Forexample, a method of treating overweight or obesity with a compositioncan alternatively entail the use of a composition in the manufacture ofa medicament for the treatment of overweight or obesity, or the use of acomposition for the treatment of overweight or obesity.

It is understood by those of skill in the art that numerous and variousmodifications can be made without departing from the spirit of thepresent invention. Therefore, it should be clearly understood that theembodiments of the present invention disclosed herein are illustrativeonly and are not intended to limit the scope of the present invention.Any reference referred to herein is incorporated by reference for thematerial discussed herein, and in its entirety.

Examples

The examples below are non-limiting and are merely representative ofvarious aspects of the invention.

Example 1 summarizes the protocol for a clinical study demonstratingthat treatment with Naltrexone SR/Bupropion SR does not increase ordecreases the occurrence of Major Adverse Cardiovascular Events (MACE)in overweight and obese subjects with cardiovascular risk factors.

APPENDIX 1 APPENDIX 1: SCHEDULE OF STUDY PROCEDURES Period: TreatmentVisit 7-13 Visit 14 Screening Lead-in Visit 3 (Wks 26, 52, (Wk 208; Endof Visit 1 Visit 2 (Day 1) Visit 4 Visit 5 Visit 6 78, 104, 130, End-of-Treatment Remote (Screening) (Wk −2) (Baseline) (Wk 2) (Wk 8) (Wk 16)156, 182) Study)⁵ Visit⁶ Contacts⁷ Informed Consent X EligibilityCriteria X X X (labs) Demographics X Medical History X Height X Weight XX X X X X X X X Waist X X X Circumference Vital Signs (BP and X X X X XX X X X HR) Concomitant X  X¹ X X Medications Pregnancy Test X (urine)²Drug Screen (urine) X Chemistry, X Hematology, Urinalysis, Lipids,HbAlc, hsCRP Electrocardiogram X Enrollment and X Lead-in RandomizationStudy Training X X  X³ Evaluation of Study X Medication and Food Diary XCompliance Treatment X Randomization MACE X X X X X X X X SAEs, AEsLeading X X X X X X X X to Discontinuation, Pregnancies Weight

Management Program Evaluation to X Continue Treatment Study Medication XX X X X X X Dispensing/Return⁴ Study Medication X X X X X X X XCompliance The visit window for Visit 3 (Day 1) is ±3 days relative toVisit 2 (Week −2). Post-baseline visit windows are ±3 days at Visit 4,±1 week at Visit 5 and 6, ±2 weeks for subsequent visits. ¹For Visits 8,10, and 12 only. ²Women of child-bearing potential (includingperi-menopausal women who have had a menstrual period within one year)only. ³Visit 7 training will focus on remote internet or telephonecontact procedures. ⁴Visit 2 = dispensing only, Visit 14/End-of-StudyVisit, and End-of-Treatment Visit = return only. ⁵Subjects with anEnd-of-Treatment Visit will not return study medication or havecompliance or concomitant medications recorded at Visit 14/End-of-StudyVisit. ⁶Subjects who discontinue study medication before Week 208 willbe asked to return to the study site for the indicated end-of-treatmentassessments, and asked to return for their remaining visits through Week208 for follow-up. ⁷After Visit 7 and through the remainder of thestudy, subjects will answer specific questions pertaining to complianceand any occurrence of hospitalization through an internet or telephonebased data collection system every 2 months between visits.Hospitalization information will be used to identify potential MACE orSAEs.

Example 2 summarizes the protocol for a clinical study demonstrating thebeneficial effect of Naltrexone SR/Bupropion SR on body weight andcardiovascular risk factors in overweight and obese subjects inconjunction with a comprehensive lifestyle intervention (CLI) programcompared minimal lifestyle intervention program.

APPENDIX 2 Schedule of Study Procedures for Example 2 Screening Visit 2Controlled Treatment Period Visit 1 (Day 1) Visit 3 Visit 4 Visit 5Visit 6 Visit 7 Visit 8 (Screen)

(Baseline)

(Wk 2) (Wk 6) (Wk 10) (Wk 16)

(Wk 20) (Wk 26)

Informed Consent X Eligibility Criteria X X Demographics X MedicalHistory X X Height X Electrocardiogram, X Physical Exam Chemistry,Hematology, X Urinalysis, Drug Screen (urine) Randomization X Weight,Vital Signs X X X X X X X X (BP and HR) Waist X X CircumferenceConcomitant X X X X X X X X Medications Review Pregnancy Test X X X X XX X X (urine)

Lipids, Glucose, X (glucose, X X X Insulin

TG

 only) Patient Reported X X X Outcome Measures (BES, ASEX, IWQOL-Lite)Query for SAEs X X X X X X Minimal Lifestyle X X Intervention (UsualCare only) Evaluation to X Continue Treatment (NB only) Review CLI  X

X X X X X  X

participaton (NB only) Study Medication  X

X X X X  X

Dispensing/Return (NB only) Study Medication X X X X X X Compliance (NBonly) The visit window between Visit 1 (Screening) and Visit 2 (Day 1,Baseline) is up to 2 weeks. Visit windows are

 days at Visit 4 and 4;

 week at Visits 5, 6, 7, and 8 relative to Visit 2.

Subjects should arrive having fasted (no food or beverage except water)overnight for at least 8 hours before this visit. Subjects shouldreceive a call from a member of the study site staff 1 to

 days prior to these visits (except Visit 1) reminding them to fast forat least

 hours prior to the visit.

Women of child-bearing potential (including peri-menopausal women whohave had a menstrual period within one year) only.

Glucose and

glycerides at Visit

 are to confirm subject eligibility. Measures at Visit

 are to obtain baseline values.

Subjects are to be registered for the CLI program and receiveinstructions at this visit.

Subjects randomized to Usual Care who switch to NB and CLI are to beregistered for the CLI program and receive instructions at this visit.

Dispensing only at this visit.

Subjects randomized to Usual Care who switch to NB are to be dispensedstudy medications at this visit. Uncontrolled Treatment Period End ofFull Visit 9 Visit 10 Visit 11 Visit 12 Visit 13 Visit 14 Visit 15Participation (Wk 32) (Wk 36) (Wk 42)¹ (Wk 46) (Wk 52)¹ (Wk 65) (Wk 78)¹Visit Weight. Vital Signs X X X X X X X X (BP, HR) Waist Circumference XX X X Concomitant X X X Medications Pregnancy Test (urine)² X X X X X XX X Lipids, Glucose, Insulin X X X Patient Repented  X³ Outcome Measures(BES, ASEX, IWQOL- Lite) Query for SAEs X X X X X X X X Evaluation toContinue X Treatment (Usual care → NB only) Review CLI X X X X X X X  X⁴participation Study Medication X X X X X X  X⁵  X⁵ Dispensing/ReturnStuds- Medication X X X X X X X X Compliance Visit windows are ±3 daysat Visit 9; ±1 week at Visits 10, 11, 12, and 13 relative to Visit 2: ±2weeks at Visit 14 and 15 relative to Visit 2. ¹Subjects should arrivehaving fasted (no food or beverage except water) overnight for at least8 hours before this visit. Subjects should receive a call from a memberof the study site staff 1 to 3 days prior to these visits reminding themto fast for at least 8 hours prior to the visit. ²Women of child-bearingpotential (including peri-menopausal women who have had a menstrualperiod within one year) only. ³To be completed if the End of FullParticipation Visit occurs during the Controlled Treatment Period. ⁴NBonly at this visit. ⁵Returning only at this visit.

indicates data missing or illegible when filed

TABLE 3 Canadian Cardiovascular Society grading scheme for anginapectoris Grade Description Grade I Ordinary physical activity does notcause angina, such as walking and climbing stairs. Angina with strenuousor rapid or prolonged exertion at work or recreation. Grade II Slightlimitation of ordinary activity. Walking or climbing stairs rapidly,walking uphill, walking or stair climbing after meals, or in cold, or inwind, or under emotional stress, or during the few hours after awaking.Walking more than two blocks on the level and climbing more than oneflight of ordinary stairs at a normal pace and in normal conditions.Grade III Marked limitation of ordinary physical activity. Walking oneor two blocks on the level and climbing one flight of stairs in normalconditions and at normal pace. Grade IV Inability to carry on anyphysical activity without discomfort, angina syndrome may be present atrest. Campeau, 1976. Available on the Canadian Cardiovascular SocietyWebsite at www.ccs.ca

TABLE 4 New York Heart Association: the stages of heart failure ClassPatient symptoms Class I (Mild) No limitation of physical activity.Ordinary physical activity does not cause undue fatigue, palpitation, ordyspnea (shortness of breath). Class II (Mild) Slight limitation ofphysical activity. Comfortable at rest, but ordinary physical activityresults in fatigue, palpitation, or dyspnea. Class III (Moderate) Markedlimitation of physical activity. Comfortable at rest, but less thanordinary activity causes fatigue, palpitation, or dyspnea. Class IV(Severe) Unable to carry out any physical activity without discomfort.Symptoms of cardiac insufficiency at rest. If any physical activity isundertaken, discomfort is increased. Available on the Heart FailureSociety of America website at www.abouthf.org

1. A method of treating a subject at increased risk of an adverse cardiovascular outcome comprising for overweight or obesity: identifying an overweight or obese subject at increased risk of an adverse cardiovascular outcome; and administering to said subject a therapeutically effective amount of sustained release naltrexone, or a pharmaceutically acceptable salt thereof, and sustained release bupropion, or a pharmaceutically acceptable salt thereof. 2-35. (canceled) 